PML-RARA mutations and ATRA resistance in pediatric acute promyelocytic leukemia

• Grant number: 22/06635-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2022
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: José Andrés Yunes
• Grantee: Mikaela Teodoro
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Associated scholarship(s): 23/04913-2 - Biochemical and biophysical characterization of PML-RARA somatic mutations, BE.EP.IC

Abstract

Leukemias are hematologic neoplastic diseases, which are characterized by the uncontrolled proliferation of hematopoietic cells and are classified according to the phenotype of the affected cell. In this study, we will focus on acute promyelocytic leukemia (APL), belonging to the group of acute myeloid leukemia (AML), subgroup M3 or M3 variant. LPA is characterized by a t(15;17) chromosomal translocation involving the PML (15q24.1) and RARA (17q21.2) genes, resulting in the formation of a chimeric transcript and the PML-RARA fusion protein. t(15;17) is present in 95% of patients with APL and the treatment of this leukemia is based on the use of all-trans retinoic acid (ATRA) combined with anthracycline chemotherapy. More recently, arsenic trioxide was incorporated into the treatment, with considerable improvement in therapeutic success. However, some patients show poor response or resistance to ATRA treatment, and studies suggest that mutations in the PML-RARA fusion transcript may be responsible for this behavior. Thus, the present study aims to analyze and identify possible mutations in PML-RARA in cases of APL positive for t(15;17) admitted for treatment at Centro Infantil Boldrini in the period between 2000 and 2020. This project was initiated by the student Beatriz Mendes Galvão (FAPESP 2020/09528-1, 11/01/2020 to 10/31/2021), who worked with PML-RARA Sanger sequencing. This time, the sequencing will be done by New Generation (NGS).(AU)